The present invention relates to novel enantiomeric compounds and pharmaceutical compositions useful in the treatment of epilepsy and other CNS disorders.
The predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized seizures are petit mal, which is associated with myoclonic jerks, akinetic seizures, transient loss of consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures and convulsions with loss of consciousness.
The mainstay of treatment for such disorders has been the long-term and consistent administration of anticonvulsant drugs. Most drugs in use are weak acids that, presumably, exert their action on neurons, glial cells or both of the central nervous system. The majority of these compounds are characterized by the presence of at least one amide unit and one or more benzene rings that are present as a phenyl group or part of a cyclic system.
Much attention has been focused upon the development of anticonvulsant drugs and today many such drugs are well known. For example, the hydantions, such as phenytoin, are useful in the control of generalized seizures and all forms of partial seizures. The oxazolidinediones, such as trimethadione and paramethadione, are used in the treatment of non-convulsive seizures. Phenacemide, a phenylacetylurea, is one of the most well known anticonvulsants employed today, while much attention has recently been dedicated to the investigation of the diazepines and piperazines. For example, U.S. Pat. Nos. 4,002,764 and 4,178,378 to Allgeier, et al. disclose esterified diazepine derivatives useful in the treatment of epilepsy and other nervous disorders. U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes a thieno [2,3-e][1,4]diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Pat. No. 4,209,516 to Heckendorn, et al. relates to triazole derivatives which exhibit anticonvulsant activity and are useful in the treatment of epilepsy and conditions of tension and agitation. U.S. Pat. No. 4,372,974 to Fish, et al. discloses a pharmaceutical formulation containing an aliphatic amino acid compound in which the carboxylic acid and primary amine are separated by three or four units. Administration of these compounds in an acid pH range are useful in the treatment of convulsion disorders and also possess anxiolytic and sedative properties.
U.S. Pat. No. 5,378,729 to Kohn, et al. discloses compounds and pharmaceutical compositions having central nervous system (CNS) activity which are useful in the treatment of epilepsy and other CNS disorders having the following general formula: 
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group, or electron donating group.
R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group and
R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Zxe2x80x94Y wherein R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group;
Z is O, S, S (O)a, NR4, PR4 or a chemical bond;
Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, or heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond, or
ZY taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7, NR4PR5R6, PR4NR5R7, 
R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R4, R5 and R6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group,
R7 is R6, COOR8 or COR8,
R8 is hydrogen, lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and
n is 1-4 and
a is 1-3.
Unfortunately, despite the many available pharmacotherapeutic agents, a significant percentage of the population with epilepsy or related disorders are poorly managed. Moreover, none of the drugs presently available are capable of achieving total seizure control, and most have disturbing side effects. Toxicities may appear upon repeated dosing that are not apparent with acute administration. Because many drugs which require chronic administration ultimately place an extra burden on the liver, including for example, liver enzyme induction or oxidative metabolism that may generate reactive species, many anticonvulsants have associated therewith liver toxicity.
Research is continuing in this area to find better and more effective anticonvulsant agents, especially for long term treatment (chronic administration). Obviously, the ideal drug is one that has high pharmacological activity, minimal side effects and is relatively non-toxic and safe to the animal that is being treated. More specifically, the ideal anticonvulsant drug is one that satisfies the following four criteria: (1) has a high anticonvulsant activity, (expressed as a low ED50); (2) has minimal neurological toxicity, (as expressed by the median toxic dose (TD50)), relative to its potency; (3) has a maximum protective index (sometimes known as selectivity or margin of safety), which measures the relationship between the doses of a drug required to produce undesired and desired effects, and is measured as the ratio between the median toxic dose and the median effective dose (TD50/ED50); and (4) is relatively safe as measured by the median lethal dose (LD50) relative to its potency and is non-toxic to the animal that is being treated, e.g., it exhibits minimal adverse effects on the remainder of the treated animal, its organs, blood, its bodily functions, etc. even at high concentrations, especially during long term chronic administration of the drug. Thus, for example, it exhibits minimal, i.e., little or no liver toxicity. Although not as critical in short term or acute administration of an anti-convulsant, since the animal may tolerate some low levels of toxicity, the fourth criteria outlined above is extremely important for an anti-convulsant which is to be taken over a long period of time (chronic administration) or in high dosage. It may be the most important factor in determining which anti-convulsant to administer to a patient, especially if chronic dosing is required. Thus, an anti-convulsant agent which has a high anti-convulsant activity, has minimal neurological toxicity and maximal P.I. (protective index) may unfortunately exhibit such toxicities which appear upon repeated high levels of administration. In such an event, acute dosing of the drug may be considered, but it would not be used in a treatment regime which requires chronic administration of the anti-convulsant. In fact, if an anti-convulsant is required for repeated dosing in a long term treatment regime, a physician may prescribe an anti-convulsant that may have weaker activity relative to a second anti-convulsant, if it exhibits relatively low toxicity to the animal. An anti-convulsant agent which meets all four criteria is very rare.
However, the present inventor has found such a group of compounds that is generally potent, exhibit minimal neurological toxicity, has a high protective index and is relatively non-toxic to the body organs, including the liver upon multiple dosing.
Accordingly, the present invention is directed to N-benzyl-2-acetamido propionamide derivatives in the R configuration having the formula: 
wherein
Ar is aryl which is unsubstituted or substituted with halo;
Q is lower alkoxy; and
Q1 is CH3.
The present invention contemplates employing the compound of Formula I in a pharmaceutical composition. Moreover, the administration of an effective amount of the present compounds in their pharmaceutically acceptable forms provides an excellent regime for the treatment of epilepsy, nervous anxiety, psychosis, insomnia, and other related central nervous disorders.
These drugs exhibit high anti-convulsant activity, minimal neurological toxicity, high P.I. and minimal toxicity. These anti-convulsants are utilized in a treatment regime requiring acute dosing, and especially chronic dosing thereof to the patient.
As shown hereinbelow, the compounds of the present invention exhibit minimal effects on liver, which is in contrast to other anti-convulsant compounds.
As used herein the term xe2x80x9calkoxyxe2x80x9d refers to an O-alkyl group attached to the main chain through an oxygen bridge, wherein alkyl is as defined hereinabove. The alkoxy groups are lower alkoxy groups containing one to six carbon atoms, and more preferably, one to three carbon atoms. The most preferred alkoxy groups are propoxy, isopropoxy, ethoxy and especially methoxy.
The term xe2x80x9carylxe2x80x9d, when used alone or in combination, refers to a phenyl group which is unsubstituted or substituted with halo.
The term halo includes fluoro, chloro, bromo, iodo and the like. The preferred halo is fluoro.
It is preferred that Q in the compound of formula I is alkoxy having 1-3 carbon atoms. The most preferred alkoxy group is propoxy, isopropoxy, ethoxy and especially methoxy.
The Ar group as defined herein, is phenyl, which may be unsubstituted or substituted as defined herein. It is most preferred that the aryl group, i.e., phenyl, is unsubstituted or substituted with only one halo group. It is more preferred that if substituted, the halo substituent is in the para or meta position. It is even more preferred that the phenyl group is unsubstituted.
Examples of the compounds of the present invention include:
(R)-N-Benzyl-2-acetamido-3-methoxy propionamide,
(R)-N-(3-Fluorobenzyl)-2-acetamido-3-methoxypropionamide,
(R)-N-(4-Fluorobenzyl)-2-acetamide-3-methoxypropionamide,
(R)-N-Benzyl-2-acetamido-3-ethoxy propionamide.
As indicated by the asterisk in formula I, the compounds of the present invention contain at least one asymmetric carbon. The stereochemistry of the asymmetric carbon at the asterisk is in the R configuration. The inventor has found that the R stereoisomer at the asymmetric carbon at the asterisk is significantly more efficacious than the corresponding S enantiomer or a racemic mixture thereof.
It is preferred that the compound of the present invention be substantially pure, i.e., substantially free from impurities. It is most preferred that the compounds of the present invention be at least 75% pure (w/w) and more preferably greater than about 90% pure (w/w) and most preferably greater than about 95% pure (w/w).
It is also preferred that the compounds of the present invention be substantially enantiomerically pure, i.e., substantially free from the corresponding S isomer. It is more preferred that the compounds of the present invention contain at least 90% (w/w) R stereoisomer, and most preferably greater than about 95% (w/w) in the R stereoisomer. Thus, the present invention contemplates compounds having at most about 10% S isomer (w/w), and even more preferably less than about 5% S isomer (w/w).
The compounds of the present invention in the R form are prepared by art recognized techniques from commercially available starting materials.
An exemplary procedure is outlined in Scheme 1 hereinbelow: 
A D serine molecule (1) is esterified under acylation conditions with an alcohol, such as acidic methanol, to provide the corresponding ester (2). 2 is reacted with ArCH2NH2, such as benzylamine, under acylation conditions to form the corresponding amide (3). Acylation of the free amino group, with an acylating derivative of 
such as acetic acid, or lower alkyl ester of acetic acid, or acetic anhydride provides the hydroxymethyl derivative, i.e., 
The enantiopurity of 4 was determined by techniques known in the art, including melting point, optical rotation and 1H NMR upon addition of an organic acid in the R-configuration, such as R(xe2x88x92)- mandelic acid. Crystallization of 4 was repeated until the desired enantiopurity thereof was achieved. The product of 4 is converted to the ether under Williamson conditions by reacting it with QX, wherein Q is as defined herein above and X is good leaving groups, such as OTs, OMs, or halide (e.g., CH3I) and the like in the presence of base (e.g., Ag2O) to form the product (5) having Formula I.
Another variation is depicted in Scheme 2. 
For example, beginning with D-serine (1), treatment with an acylating derivative of acetic acid such as acetic anhydride in acetic acid, gives the corresponding amide 6 which is then reacted with ArCH2NH2 under mixed anhydride coupling reaction conditions, as described by Anderson, et al., in JACS, 1967, 89, 5012-5017, the contents of which are incorporated herein by reference, to give the corresponding compound of the formula: 
e.g., 7. Alkylation of this R-product in the presence of base under Williamson conditions, such as methyl iodide in Ag2O, provides a product of Formula I (8).
An alternative route is depicted in Scheme 3. 
D Serine (1) is protected with a N-protecting group known in the art, by standard techniques. Thus, for example, it is reacted with carbobenzoxy chloride (CBZ-cl, benzyl chloroformate) generating the N-protected CBZ-D-serine adduct 9. The product serine adduct is converted to the corresponding ether under Williamson conditions by reacting it with QX wherein Q and X are defined hereinabove (e.g., CH3I) in the presence of base (e.g., Ag20) to form an ether 10. Under these conditions, the acid is also esterified. Subsequent hydrolysis of the ester group in 10 permits amide coupling with ArCH2 NH2 using amide coupling methodology (e.g., mixed anhydride 1,1xe2x80x2 Carbonyldiimidazole) to give the amide 12. Deprotection of the N-protecting group provide the free amine 13 which is then reacted with an acylating agent such as acetic anhydride in base, (e.g., pyridine) to provide the product (R)-8.
If necessary, in any of the procedures described hereinabove, the optical purity of the product may be enhanced by further separation of the S enantiomer from the R enantiomer, by standard techniques known in the art, such as chiral chromatography using a standard chiral support known in the art.
Alternatively, in any of the procedures provided hereinabove, a racemic D serine may be utilized as the starting material. Following the procedures in any of the schemes outlined hereinabove would provide the racemic mixture, which can be resolved into the R isomer by standard techniques known in the art such as chiral chromatography.
The active ingredients of the therapeutic compositions and the compounds of the present invention exhibit excellent anticonvulsant activity when administered in amounts ranging from about 1 mg to about 100 mg per kilogram of body weight per day. This dosage regimen may be adjusted by the physician to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that the active compound may be administered in an convenient manner such as by the oral, intravenous (where water soluble), intramuscular or subcutaneous routes.
The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly into the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 100 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition of materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. For example, sustained release dosage forms are contemplated wherein the active ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.
The active compound may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifics for the novel dosage unit forms of the invention are dictated by and directly, dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore described. A unit dosage form can, for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg. Expressed in proportions, the active compound is generally present in from about 1 to about 750 mg/ml of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Unless indicated to the contrary, percentages are by weight.
As used herein, the term lower alkyl refers to an alkyl group containing 1-6 carbon atoms which may be straight chained or branched.